Patients with inherited enamel or dentin defects, because of the disfiguring appearance of their teeth, have low self-esteem and perceive themselves as having an inferior quality of life. Their teeth are painful: they avoid hot foods, cold drinks and ice cream. One 9-year-old girl with defective enamel told us that ice cream hurts like when you bump your elbow wrong. Advancing our understanding of normal and pathological tooth formation provides the best long-term hope for improvements in the diagnosis, treatment, and cure of inherited dental diseases. In this study we test the following three Hypotheses: 1) Defects in the genes encoding specialized enamel and dentin proteins cause amelogenesis imperfecta and dentinogenesis imperfecta or dentin dysplasia, respectively. 2) Genome-wide searches and candidate gene approaches can efficiently identify genes involved in the etiology of inherited dental disorders. 3) Characterizing the ameloblast transcriptome and the enamel and dentin proteomes will identify proteins critical for enamel and dentin formation and improve our understanding of the molecular mechanisms of normal and pathologic tooth formation. To test these hypotheses we propose the following two Specific Aims: SA 1: Identify genes and mutations that cause inherited defects of enamel and dentin. SA 2: Isolate and characterize molecules in the extracellular matrices of developing enamel and dentin. Approach: We recruit families with non-syndromic inherited defects of enamel and dentin, characterize their phenotypes, and perform mutation analyses on candidate genes to identify their causes. When possible we will perform genome-wide searches or joined analyses to link a small part of the genome to the dental disease. New candidate genes are identified by characterizing the ameloblast transcriptome and by performing proteomic analyses of the enamel and dentin extracellular matrices, which also characterize the proteins' structures. Significance: Identifying the full set of genes that cause non-syndromic inherited defects of enamel and dentin will change the ways we classify, diagnose, and perceive these disorders. The list of candidate genes that might cause the disease in a presenting family will be prioritized using established genoptype- phenotype correlations. As treatment outcomes are evaluated in persons with defined mutations, the success or failure of procedures such as enamel or dentin bonding may correlate with which gene is mutated, leading to improvements in treatment planning. Future genetic analyses may link genetic changes in these genes to susceptibility for dental caries and provide insights into mechanisms of tooth formation.